(a) Field of the Invention
The invention relates to a method of preparation of polymer microparticles free of organic solvent traces.
(b) Description of Prior Art
There is a substantial interest in the preparation of polymer microparticles in the micrometer and submicrometer ranges, because of their potential applications. These kind of particles are produced by various manufacturing processes including suspension, emulsion and dispersion polymerization in addition to the well known solvent evaporation-based method. In the biotechnological field, polymer microparticles have attracted increasing attention as carrier matrices in a wide variety of applications, namely affinity chromatography, immobilization technologies, drug delivery systems, nuclear imaging and cell culturing (Rembaum A. and Toke Z. A., Eds., Microspheres: Medical and Biological Applications, CRC Press, Boca Raton, Fla., 1988; Mosbach K., 1988, Methods Enzymol., 137:443; Arshady R., 1993, Biomaterials, 14:5).
Up to now, all methods reported that the fabrication of such microparticles requires a solution media, since they necessarily involve preliminary dissolution of polymers or relative monomers depending on the technique.
Aliphatic polyesters are preferred polymers for the preparation of biodegradable microparticles as devices for drug delivery and cell culturing. Such a preparation is often carried out in presence of CH.sub.2 Cl.sub.2 or CH.sub.3 Cl as organic solvent, and poly(vinyl alcohol), PVA, as surfactant. Accordingly, one cannot underestimate the toxicity risks associated with the solvent and surfactant residues remaining adsorbed on the microparticles inner and outer surfaces. The surfactant problem may be solved by using other surfactants, such as methyl cellulose or poly(ethylene oxide) Sorbitan.TM. monoalkaneoates (Tween.TM.) instead of PVA (U.S. Pat. No. 4,933,105 in the name of Fong J. W.; Jalil R. and Nixon J. R., 1990, J. Microencapsul., 7:297; Bodmeier R. and McGinity J. W., 1987, J. Microencapsul., 4:279).
More recent patent gets around the surfactant problem by using PLA or PLGA oligomer to prepare microparticles of PLA and PLGA polymers (Vert M. et al., International Patent Application published under No. WO93/25191 on Dec. 23, 1993). However, the solvent problem seems to be too difficult to overcome, and thus its use remains an important drawback of the prior art method.
Both mentioned patents are based on solvent-evaporation method to produce microparticles of PLA or PLGA as matrices for drugs or cells. The employed method consists to dissolve desired polymer in CH.sub.2 Cl.sub.2 or CH.sub.3 Cl, after which the resultant solution is emulsified in aqueous media containing a surfactant as stabilizing agent for the dispersed phase. Once the emulsion is formed the organic solvent is taken off by simple evaporation. The first patent uses Na-Oleate as surfactant, while in the second one, the microparticles are prepared in presence of PLA and PLGA oligomers, which allowed them to be considered surfactant-free.
It would be highly desirable to be provided with an alternative method aiming to produce microparticles from melted polymers, which avoid using organic solvents which are mostly toxic. Such a method is expected to receive a particular attention in biotechnological field.